There are more than 420,000 patients receiving maintenance hemodialysis therapy in the United States, which is estimated to rise to over 500,000 patients by 2020. There are an estimated 45,500 veterans receiving hemodialysis, of which over 3,000 enrolled veterans were receiving dialysis at VA facilities in FY 2013. Over the last decade, there have been no therapies proven to significantly lower the mortality and morbidity risk for these patients. One of the most important determinants of this poor clinical outcome is protein energy wasting, a highly prevalent nutritional and metabolic abnormality characterized by increased protein breakdown in the skeletal muscle compartment. Our group has shown that two well-recognized and interrelated metabolic abnormalities, insulin resistance and persistent inflammation, are likely to play a critical role in the pathogenesis of protein energy wasting and related nutritional and metabolic abnormalities. Our preliminary data show that in maintenance hemodialysis (MHD) patients 1) There is an inadequate response to protein anabolic actions of insulin; 2) Persistent systemic inflammation is strongly and independently associated with skeletal muscle net protein balance; and 3) Pharmacological modulation of systemic inflammation and insulin resistance partially, but not fully, reverse net protein catabolism. It was demonstrated that non-osmotic sodium (Na) is stored in skin and muscle without commensurate water retention, which leads to local immune-cell activation and accelerated pro-inflammatory status. Our preliminary data show that the skin and muscle Na+ contents, derived by 23Na magnetic resonance imaging (MRI) are substantially higher in MHD patients compared to matched healthy controls. We also showed that increased skin and muscle Na concentrations are significantly associated with increased inflammatory response and decreased peripheral insulin sensitivity, in patients on MHD. These data suggest that tissue Na content, immune pathways and insulin resistance are closely linked and could lead to increased risk for protein energy wasting in MHD patients. It was reported that standard 4-hour conventional hemodialysis provides significant Na removal from muscle and skin suggesting that tissue Na and water content could be modulated by modulating hemodialysis prescription. The overall goal of this application is to elucidate the mechanisms by which tissue sodium accumulation, persistent immune system activation and insulin resistance influence the development of protein energy wasting in MHD patients. We hypothesize that the skin and muscle tissue sodium accumulation is a critical mechanism by which chronic inflammatory response and insulin resistance, alone or in combination, lead to protein energy wasting in MHD patients. Specific Aim 1: To test the hypothesis that excessive Na accumulation in the skeletal muscle and skin leads to local and systemic inflammation that result in resistance to metabolic effects of insulin in MHD patients. We will achieve this aim by examining tissue Na content and net protein balance (primary outcome), markers of inflammation and macronutrient (glucose and amino acid) disposal rates and in 60 MHD patients and 30 frequency matched age, gender, race and body mass index controls without kidney disease. Specific Aim 2: To test the hypothesis that removal of tissue sodium by modulating hemodialysis prescription would improve metabolic milieu and protein energy wasting in MHD patients. We will achieve this goal through a cross-over randomized clinical trial whereby dialysate sodium concentrations will be modulated (138 mEq/L versus 132 mEq/L, 4 weeks each) to remove 10% of baseline skeletal muscle Na content in the setting of stable sodium intake by diet. Our primary outcomes will be markers of net protein balance, inflammation, and macronutrient disposal rates. If successful, our proposed studies will have great potential to influence clinical practices in MHD patients because the proposed intervention protocol would be easily accessible and could ultimately lead to improvements in the hospitalization and death rates with great impact on Veterans' Health Care and make important contributions to the research mission of the Department of Veterans Administration.